HIV-1 nef

A team of researchers has successfully modified a naturally occurring chemical compound in the lab, resulting in advanced lead compounds with anti-HIV activity. A team of University of Michigan researchers has successfully modified a naturally occurring chemical compound in the lab, resulting in advanced lead compounds with anti-HIV activity. Their results, published March 7 in the Journal of Medicinal Chemistry, offer a new path forward in the development of drugs that could potentially help cure -- rather than treat -- HIV. Although effective treatments are available to manage HIV, a cure has remained elusive due to the virus's ability to hide from the immune system, lying dormant in reservoirs of infected cells. "With most viruses, when people get infected, they get sick for a while and then the immune system kicks in and the virus is cleared," said Kathleen Collins, professor of microbiology and immunology at the U-M Medical School. "But with HIV, once a patient is infected, that virus will persist for their entire life -- meaning they must remain on treatments indefinitely." One key to HIV's ability to remain hidden in patients' cells is a protein that the virus makes, called Nef. This protein shuts down a system that the cell would normally use to alert the immune system to an infection, thus preventing the immune cells from recognizing and clearing the virus. Collins and her lab have studied this protein for more than 15 years, investigating how it works and how it can be disabled. She and David Sherman, professor at the U-M Life Sciences Institute, previously discovered that a chemical found in nature can inhibit HIV Nef, allowing the immune system to find and eliminate virally infected cells: a compound called concanamycin A (CMA), which is produced by a soil-derived microorganism. In its natural form, however, CMA presents several challenges as a potential therapeutic. The first challenge the team had to overcome was supply. While CMA is a naturally occurring compound, the original bacteria that produces it does so in quantities far too small to be useful for testing and modification in the lab. Another major challenge with developing CMA as an anti-HIV drug is that Nef is not CMA's primary target. "CMA's main job in human cells is to inhibit an enzyme called V-ATPase, which we absolutely do not want to block in this case," said Sherman, who is also a professor at the U-M College of Pharmacy, Medical School, and College of Literature, Science, and the Arts. "So, we needed to find a way to modify CMA's activity, widening the effective dosage gap between when it starts to inhibit the target we're aiming for -- HIV Nef -- without affecting V-ATPase, its typical cellular target." With this latest research, the team has overcome both of these challenges. Using bioengineering, Sherman's team was able to develop a bacterial strain that increased CMA production 2,000-fold. Synthetic chemists in the lab then created more than 70 new variations of the compound, swapping out different chemical groups, to test for their potency against HIV Nef. Collins' lab team ran the new compounds through a battery of tests to measure their toxicity to cells, as well as how they affected the activities of both HIV Nef and V-ATPase. "Even though we know that CMA is extremely active against the HIV Nef protein, all drugs have side effects," said Collins, also a professor of internal medicine at the Medical School. "And so we wanted to ensure we've done everything we can to minimize the side effect pro the drug before we consider putting it into an animal or human." The team now has several CMA analogs that show high potency in blocking HIV Nef at very low dosage levels, without interrupting off-target effects or causing toxicity in human cells. They caution, however, that several important steps remain before the compounds would be ready for further testing in a clinical setting. "We are really encouraged, though, because our groups have solved some very important problems," Sherman said. "We have engineered microorganisms to produce sustainable supplies of the natural product molecules and have really good chemical methods to make new analogs. And we have the methodologies in place to continue tracking the critical toxicity and potency parameters to further reduce off-target effects." The research was supported by the National Institutes of Health. Other study authors are: Morgan McCauley, Matthew Huston, Alanna Condren, Filipa Pereira, Joel Cline, Marianne Yaple-Maresh, Mark Painter, Gretchen Zimmerman, Andrew Robertson, Nolan Carney, Christopher Goodall and Valeri Terry of U-M and Rolf Mu?ller of Hemholtz Institute for Pharmaceutical Research, Germany.

A pharmacy associate professor has developed a novel nanomedicine loaded with genetic material called small interfering RNAs (siRNA) to fight human immunodeficiency virus (HIV) using gene therapy. Society learned about the value of mRNA during the COVID-19 pandemic when we saw scientists and medical professionals harness its power to deliver a vaccine for the virus within a year. Now, University of Waterloo pharmacy associate professor Emmanuel Ho has developed a novel nanomedicine loaded with genetic material called small interfering RNAs (siRNA) to fight human immunodeficiency virus (HIV) using gene therapy. These siRNAs regulate which genes or proteins are turned on or off in our cells and showed a 73 per cent reduction in HIV replication. "This opens the door for new therapeutics in the fight against HIV," said Dr. Ho, who is among Waterloo's researchers and entrepreneurs leading health innovation in Canada. Autophagy, also known as the body's recycling process, plays an important role in our body to eliminate microbes such as viruses and bacteria inside cells. HIV is quite smart and produces a protein, Nef, that prevents cells from activating autophagy. This is the first research to develop a combination nanomedicine that can reactivate autophagy and prevent HIV entry into cells, allowing our body to re-initiate its defence system. Additionally, HIV has a gene, CCR5, that allows the virus to enter a cell. The siRNAs target both Nef and CCR5 to reduce HIV infection. This nanomedicine is intended to be applied vaginally to protect against sexual transmission of HIV. As a result, the nanomedicine is designed to be stable without leakage of siRNAs in the acidic vaginal environment but release the siRNA once inside cells. "Viruses are smart. They produce Nef proteins to prevent autophagy from occurring," Ho said. "Our process allows our body to fight the viral infection without needing additional drugs," Ho confirms that the next steps include further optimizing the process and improving our understanding of how autophagy plays a role in how our cells protect us from viruses. "We also hope this will shed some light to develop more alternative approaches to effectively reduce antimicrobial resistance," Ho said.

LOS GATOS, Calif., Dec. 15, 2023 (GLOBE NEWSWIRE) -- Aridis Pharmaceuticals, Inc. (OTC QB: ARDS), a biopharmaceutical company focused on the discovery and development of novel anti-infective therapies for treating life-threatening infections, today announced that its 2023 Annual Meeting of Stockholders ("Annual Meeting"), scheduled for Friday, December 15, 2023, was convened and adjourned, without any business being conducted, due to lack of the requisite quorum. The Annual Meeting has been adjourned to 9:00 AM local time on January 12, 2024 at the Company’s offices located at 983 University Avenue, Bldg. B, Los Gatos, CA 95032, to allow additional time for stockholders to vote on the proposals set forth in Aridis’s definitive proxy statement on Schedule 14A, filed with the Securities and Exchange Commission on November 3, 3023. The record date for the Annual Meeting remains November 2, 2023. Stockholders who have previously submitted their proxy or otherwise voted and who do not want to change their vote need not take any action. Company stockholders as of the November 2, 2023 record date can vote, even if they have subsequently sold their shares. The Company’s board of directors and management respectfully request all such holders as of the record date to please vote your proxies as soon as possible. No changes have been made in the proposals to be voted on by stockholders at the Annual Meeting. The Company strongly advises all of its stockholders to read the proxy statement and other proxy materials relating to the Annual Meeting because they contain important information. Such proxy materials are available at no charge on the Securities and Exchange Commission's website at www.sec.gov. In addition, copies of the Proxy Statement and other documents may be obtained free of charge by accessing http://annualgeneralmeetings.com/ards2023 or by contacting the Company’s Corporate Secretary at 408-385-1742 or by mail to Corporate Secretary, Aridis Pharmaceuticals, Inc., 983 University Avenue, Bldg. B, Los Gatos, CA 95032. About Aridis Pharmaceuticals, Inc. Aridis Pharmaceuticals, Inc. discovers and develops anti-infectives to be used as first-line treatments to combat antimicrobial resistance (AMR) and viral pandemics. The Company is utilizing its proprietary ʎPEX TM and MabIgX® technology platforms to rapidly identify rare, potent antibody-producing B-cells from patients who have successfully overcome an infection, and to rapidly manufacture mAbs for therapeutic treatment of critical infections. These mAbs are already of human origin and functionally optimized by the natural human immune system for high potency. Hence, they are already fit-for-purpose and do not require further engineering optimization to achieve full functionality. The Company has generated multiple clinical stage mAbs targeting bacteria that cause life-threatening infections such as ventilator associated pneumonia (VAP) and hospital acquired pneumonia (HAP), in addition to preclinical stage antibacterial and antiviral mAbs. The use of mAbs as anti-infective treatments represents an innovative therapeutic approach that harnesses the human immune system to fight infections and is designed to overcome the deficiencies associated with the current standard of care, which is broad spectrum antibiotics. Such deficiencies include, but are not limited to, increasing drug resistance, short duration of efficacy, disruption of the normal flora of the human microbiome and lack of differentiation among current treatments. The mAb portfolio is complemented by a non-antibiotic novel mechanism small molecule anti-infective candidate being developed to treat lung infections in cystic fibrosis patients. The Company’s pipeline is highlighted below: Aridis' Pipeline AR-301 (VAP). AR-301 is a fully human IgG1 mAb currently in Phase 3 clinical development targeting gram-positive S. aureus alpha-toxin in VAP patients. AR-501 (cystic fibrosis). AR-501 is an inhaled formulation of gallium citrate with broad-spectrum anti-infective activity being developed to treat chronic lung infections in cystic fibrosis patients. This program is currently in a Phase 2a clinical study in CF patients. AR-320 (VAP). AR-320 is a fully human mAb targeting S. aureus alpha-toxin for prevention of VAP. Statistically significant Phase 2 data in the target population of those ≤ 65 years of age was published in the September 2021 Lancet Infectious Diseases journal. AR-701 (COVID-19). AR-701 is a cocktail of fully human mAbs discovered from convalescent COVID-19 patients that target multiple sites on the spike proteins of the SARS-CoV-2 virus. AR-101 (HAP). AR-101 is a fully human IgM mAb in Phase 2 clinical development targeting Pseudomonas aeruginosa liposaccharides serotype O11, which accounts for approximately 22% of all P. aeruginosa hospital acquired pneumonia cases worldwide. This program is licensed to the Serum Institute of India and Shenzhen Arimab. AR-201 (RSV infection). AR-201 is a fully human IgG1 mAb directed against the F-protein of diverse clinical isolates of respiratory syncytial virus (RSV). This program is licensed exclusively to the Serum Institute of India. AR-401 (blood stream infections). AR-401 is a fully human mAb preclinical program aimed at treating infections caused by gram-negative Acinetobacter baumannii. For additional information on Aridis Pharmaceuticals, please visit https://aridispharma.com/. Forward-Looking Statements Certain statements in this press release are forward-looking statements that involve a number of risks and uncertainties. These statements may be identified by the use of words such as "anticipate," "believe," "forecast," "estimated" and "intend" or other similar terms or expressions that concern Aridis' expectations, strategy, plans or intentions. These forward-looking statements are based on Aridis' current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, the need for additional financing, the timing of regulatory submissions, Aridis' ability to obtain and maintain regulatory approval of its existing product candidates and any other product candidates it may develop, approvals for clinical trials may be delayed or withheld by regulatory agencies, risks relating to the timing and costs of clinical trials, risks associated with obtaining funding from third parties, management and employee operations and execution risks, loss of key personnel, competition, risks related to market acceptance of products, intellectual property risks, risks related to business interruptions, including the outbreak of COVID-19 coronavirus, which could seriously harm our financial condition and increase our costs and expenses, risks associated with the uncertainty of future financial results, Aridis' ability to attract collaborators and partners and risks associated with Aridis' reliance on third party organizations. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various important factors, including, without limitation, market conditions and the factors described under the caption "Risk Factors" in Aridis' 10-K for the year ended December 31, 2022, and Aridis' other filings made with the Securities and Exchange Commission. Forward-looking statements included herein are made as of the date hereof, and Aridis does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances. Contact: Investor RelationsDave Gentry, CEORedChip CompaniesARDS@redchip.com SOURCE Aridis Pharmaceuticals, Inc.